This paper presents a simplified methodology for predicting the response of buildings irregular in elevation, based on the non-linear dynamic multi-modal spectral seismic response of an equivalent simplified MDOF linear system. Making use of the MDOF model, it is also proposed a methodology for the optimum strengthening design of buildings, based on convex approximation methods. Three structural upgrading optimization problems (SUOPs) are implemented. The proposed models are validated against the results of a series of PsD tests carried out on a full-scale four-storey RC structure, representative of the construction practice in southern Mediterranean countries in Europe until the late 1960s.